In many therapeutic, medical and veterinary programs, it is desirable and necessary to provide for the slow release of a beneficial agent to a living being at a controlled rate over a prolonged period of time. In many cases, it is desirable that the rate of release of the agent be constant or have a zero order time dependence in order that the living being continuously receives a uniform amount of beneficial agent.
Different approaches have been tried to obtain a sustained-release device which would release a beneficial agent at a controlled rate. One method used is to mix the drug with a carrier material that is gradually broken down by body fluids, the drug being released as the carrier disintegrates. Waxes, oils, fats and soluble polymers are some materials that have been used as the carriers in these systems. Constant release or zero order release has not been obtained by this method since as the carrier disintegrates, the surface area of the dosage unit decreases, exposing smaller quantities of the carrier to the surrounding body fluids and thus decreasing the release rate of the medicament.
Another approach, set out in U.S. Pat. No. 3,113,076, is to design a solid tablet form with at least one aperture so that during disintegration of the tablet, the total area subject to disintegration and release of active medicament remains relatively constant. The constant release is obtained because the surface area available to release the medicament decreases on the outer surface as it disintegrates and increases on the inner surface as that surface disintegrates, keeping the total surface area available for release relatively constant. This type of disintegrating tablet, however, does not last for a prolonged period of time and is meant only for oral administration rather than for implantation or insertion into body cavities. In one embodiment, U.S. Pat. No. 3,113,076 provides for the outer surface of the tablet to be coated with an insoluble material so that the disintegration occurs only at the inner surface. This, however, eliminates the constant release advantage, for the rate of release of the medicament will increase as the inner surface area increases with the widening disintegration of the material from the center outward.
U.S. Pat. No. 3,851,648, issued to Brooke, discloses another approach to the zero-order release problem wherein the rate of release is achieved by the configuration of a cavity within a delivery device and a slot which connects the cavity and the exterior of the device. The configuration is such as to provide an increasing surface area of diffusible substance exposed to the fluid medium within the container as the length of the path through which the dissolved substance must diffuse to reach the exterior increases. The device of the invention, an implant, is cylindrical in shape with a rectangular slot lengthwise on one side which communicates with an internal cavity, the cross-section of which is shaped like a slice of pie. This implant is quite complicated to make and different medicaments will require different sized slots and cavities to retain the zero order release advantage. Thus, the device of this invention requires various manipulations and calculations before it can be prepared in the proper size and configuration to disperse a specific desired medicament at a substantially constant rate. The suggested material for the container is stainless steel, which may cause problems in fabricating the device to meet certain specifications and may cause a negative reaction when implanted into a living being.
U.S. Pat. No. 3,146,169, issued to Stephenson and Spence, represents an attempt to achieve constant rate release from a tablet composition by covering the medicament portion with an inert portion and having a hole through the inert portion into the medicament. This method is unsatisfactory in that it provides a reservoir system wherein the release rate will only be constant as long as the medicament portion stays saturated with the drug to be released. After the medicament portion is no longer saturated with the drug, the release rate will drop off rapidly. Thus, the order of release is controlled not by the type of device and the drug employed, but by the concentration of the drug inside and outside of the device.
The object of the invention is to provide a simple, easily manufactured device for the controlled, substantially constant release of beneficial agent.
A further object of the invention is to provide a device for the release of a beneficial agent in a living being wherein the release will continue for a prolonged period of time.
A still further object of the invention is to provide devices which can be conveniently produced for the release of a variety of beneficial agents.
A still further object of the invention is to provide a biocompatible device which can be implanted, inserted into a body cavity of a living being or orally ingested by a living being.